tbuckley/cabot-search huggingface dataset:
Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC
Authors: Chenchen Li, Bo Liu, Jingyi Xu, Bin Jing, Lijie Guo, Liyong Wang, Milin Wang, Haochen Zhang, Qianqian He, Xin Yu, Yan Zhang, Zhi-Qing David Xu, Yutao Yang
Journal: Theranostics (2023)

Background:Stress is an important risk factor to induce psychiatric disorders such as depression.Phloretin (PHL), a natural dihydrochalcone compound, has been shown to exhibit anti-inflammatory and anti-oxidative effects.However, the impact of PHL on the depression and the underlying mechanism remain unclear.Methods: The animal behavior tests were used to determine the protective of PHL on the chronic mild stress (CMS)-induced depression-like behaviors.The Magnetic Resonance Imaging (MRI), electron microscopy analysis, fiber photometry, electrophysiology, and Structure Illumination Microscopy (SIM) were used to investigate the protective of PHL on the structural and functional impairments induced by CMS exposure in the mPFC.The RNA sequencing, western blot, reporter gene assay, and chromatin immunoprecipitation were adopted to investigate the mechanisms.Results: We showed that PHL efficiently prevented the CMS-induced depressive-like behaviors.Moreover, PHL not only attenuated the decrease of synapse losses but also improved the dendritic spine density and neuronal activity in the mPFC after CMS exposure.Furthermore, PHL remarkably inhibited the CMS-induced microglial activation and phagocytic activity in the mPFC.In addition, we demonstrated that PHL decreased the CMS-induced synapse losses by inhibiting the deposition of complement C3 deposition onto synapses and subsequent microglia-mediated synaptic engulfment.Finally, we revealed that PHL inhibited the NF-κB-C3 axis to display neuroprotective effects. Conclusions:Our results indicate that PHL represses the NF-κB-C3 axis and subsequent microglia-mediated synaptic engulfment to protect against CMS-induced depression in the mPFC.
Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression
Authors: Kuo Zhang, Fan Wang, Mengying Zhai, Meiyao He, Yuxuan Hu, Lijin Feng, Yuting Li, Jingyu Yang, Chunfu Wu
Journal: Theranostics (2023)

Background: Depression is a mental disorder that poses a serious threat to human health.Adult hippocampal neurogenesis (AHN) is closely associated with the efficacy of antidepressants.Chronic treatment with corticosterone (CORT), a well-validated pharmacological stressor, induces depressive-like behaviors and suppresses AHN in experimental animals.However, the possible mechanisms of chronic CORT action remain elusive.Methods: A chronic CORT treatment (0.1 mg/mL, drinking water for 4 weeks) was applied to prepare a mouse model of depression.Immunofluorescence was performed to analyze the hippocampal neurogenesis lineage, and immunoblotting, immunofluorescence, electron microscopy, and adeno-associated virus (AAV) expressing a pH-sensitive tandemly tagged light chain 3 (LC3) protein were used to analyze neuronal autophagy.AAV-hSyn-miR30-shRNA was used to knock down autophagy-related gene 5 (Atg5) expression in the neurons.Results: Chronic CORT induces depressive-like behaviors and decreases the expression of neuronal brain-derived neurotrophic factor (BDNF) in the dentate gyrus (DG) of the hippocampus in mice.Moreover, it markedly diminishes the proliferation of neural stem cells (NSCs), neural progenitor cells, and neuroblasts and impairs the survival and migration of newborn immature and mature neurons in the DG, which may be attributed to changes in the cell cycle kinetics and induction of NSCs apoptosis.Furthermore, chronic CORT induces hyperactive neuronal autophagy in the DG, possibly by increasing the expression of ATG5 and causing excess lysosomal degradation of BDNF in neurons.Notably, inhibiting hyperactive neuronal autophagy in the DG of mice by knocking down Atg5 in neurons using RNA interference reverses the decrease of neuronal BDNF expression, rescues AHN, and exerts antidepressant effects.Conclusion: Our findings reveal a neuronal autophagy-dependent mechanism that links chronic CORT to reduced neuronal BDNF levels, AHN suppression and depressive-like behavior in mice.In addition, our results provide insights for treating depression by targeting neuronal autophagy in the DG of the hippocampus.
Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair
Authors: Diane Bruyere, Patrick Roncarati, Alizee Lebeau, Thomas Lerho, Florian Poulain, Elodie Hendrick, Charlotte Pilard, Celia Reynders, Marie Ancion, Margaux Luyckx, Michael Renard, Yves Jacob, Jean-Claude Twizere, Raphael Peiffer, Olivier Peulen, Philippe Delvenne, Pascale Hubert, Alison McBride, Nicolas Gillet, Murielle Masson, Michael Herfs
Journal: Theranostics (2023)

Rationale: Whatever the mucosa primary infected, HPV-positive cancers are traditionally associated with a favorable outcome, attributable to a high sensitivity to radiation therapy.However, the direct impact of viral E6/E7 oncoproteins on the intrinsic cellular radiosensitivity (and, globally, on host DNA repair) remains mostly speculative.Methods: Using several isogenic cell models expressing HPV16 E6 and/or E7, the effect of viral oncoproteins on global DNA damage response was first investigated by in vitro/in vivo approaches.The binary interactome of each individual HPV oncoprotein with factors involved in the various host DNA damage/repair mechanisms was then precisely mapped by Gaussia princeps luciferase complementation assay (and validated by co-immunoprecipitation).The stability/half-life of protein targets for HPV E6 and/or E7 as well as their subcellular localizations were determined.At last, the host genome integrity following E6/E7 expression and the synergy between radiotherapy and compounds targeting DNA repair were analyzed.Results: We first showed that the sole expression of one viral oncoprotein from HPV16 was able to significantly increase the sensitivity to irradiation of cells without affecting their basal viability parameters.In total, 10 novel targets (CHEK2, CLK2, CLK2/3, ERCC3, MNAT1, PER1, RMI1, RPA1, UVSSA and XRCC6) for E6 and 11 (ALKBH2, CHEK2, DNA2, DUT, ENDOV, ERCC3, PARP3, PMS1, PNKP, POLDIP2 and RBBP8) for E7 were identified.Importantly, not degraded following their interaction with E6 or E7, these proteins have been shown to be less linked to host DNA and to colocalize with HPV replication foci, denoting their crucial implication in viral life cycle.Finally, we found that E6/E7 oncoproteins globally jeopardize host genome integrity, increase the cellular sensitivity to DNA repair inhibitors and enhance their synergy with radiotherapy.Conclusion: Taken together, our findings provide a molecular insight into the direct hijacking of host DNA damage/repair responses by HPV oncoproteins, demonstrate the significant impact of this phenomenon on both intrinsic cellular radiosensitivity and host DNA integrity and suggest novel connected therapeutic vulnerabilities.
When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy
Authors: Antonio Tapia-Galisteo, Marta Compte, Luis Álvarez-Vallina, Laura Sanz
Journal: Theranostics (2023)

Despite the clinical success of the first bispecific antibody approved by the FDA against B cell malignancies (blinatumomab), many obstacles remain such as dosing, treatment resistance, and modest efficacy in solid tumors.To overcome these limitations, considerable efforts have been dedicated to the development of multispecific antibodies, opening up new avenues to address both the complex biology of cancer and the onset of anti-tumoral immune responses.Simultaneous targeting of two tumor-associated antigens is presumed to enhance cancer cell selectivity and reduce immune escape.Co-engagement of CD3, along with agonists of co-stimulatory molecules or antagonists of co-inhibitory immune checkpoint receptors in a single molecule, may revert T cell exhaustion.Similarly, targeting of two activating receptors in NK cells may improve their cytotoxic potency.And these are only examples of the potential of antibody-based molecular entities engaging three (or more) relevant targets.From the perspective of health care costs, multispecific antibodies are appealing, since a similar (or superior) therapeutic effect could be obtained with a single therapeutic agent as with a combination of different monoclonal antibodies.Despite challenges in production, multispecific antibodies are endowed with unprecedented properties, which may render them more potent biologics for cancer therapy.
Targeted and responsive biomaterials in osteoarthritis
Authors: Jiadong Li, Hao Zhang, Yafei Han, Yan Hu, Zhen Geng, Jiacan Su
Journal: Theranostics (2023)

Osteoarthritis (OA) is a degenerative disease characterized by loss of articular cartilage and chronic inflammation, involving multiple cellular dysfunctions and tissue lesions.The non-vascular environment and dense cartilage matrix in the joints tend to block drug penetration, resulting in low drug bioavailability.There is a desire to develop safer and more effective OA therapies to meet the challenges of an aging world population in the future.Biomaterials have achieved satisfactory results in improving drug targeting, prolonging the duration of action, and achieving precision therapy.This article reviews the current basic understanding of the pathological mechanisms and clinical treatment dilemmas of OA, summarizes and discusses the advances for different kinds of targeted and responsive biomaterials in OA, seeking to provide new perspectives for the treatment of OA.Subsequently, limitations and challenges in clinical translation and biosafety are analyzed to guide the development of future therapeutic strategies for OA.As the need for precision medicine rises over time, emerging multifunctional biomaterials based on tissue targeting and controlled release will become an irreplaceable part of OA management.
Multimarkers of metabolic malnutrition and inflammation and their association with mortality risk in cardiac catheterisation patients: a prospective, longitudinal, observational, cohort study
Authors: James D Otvos, Irina Shalaurova, Heidi T May, Joseph B Muhlestein, John T Wilkins, Robert W McGarrah, William E Kraus
Journal: The Lancet Healthy Longevity (2023)
Hepatic PTP4A1 ameliorates high-fat diet-induced hepatosteatosis and hyperglycemia by the activation of the CREBH/FGF21 axis
Authors: Byungtae Hwang, Min-Gi Kwon, Min Ji Cho, Nam-Kyung Lee, Jangwook Lee, Jeong Woong Lee, Kyoung-Jin Oh, Kwang-Hee Bae, Jung Hwan Hwang, Jeong-Ki Min, Jong-Gil Park
Journal: Theranostics (2023)

Precise regulation of kinases and phosphatases is crucial for human metabolic homeostasis.This study aimed to investigate the roles and molecular mechanisms of protein tyrosine phosphatase type IVA1 (PTP4A1) in regulating hepatosteatosis and glucose homeostasis.Method: Ptp4a1 -/-mice, adeno-associated virus encoding Ptp4a1 under liver-specific promoter, adenovirus encoding Fgf21, and primary hepatocytes were used to evaluate PTP4A1-mediated regulation in the hepatosteatosis and glucose homeostasis.Glucose tolerance test, insulin tolerance test, 2-deoxyglucose uptake assay, and hyperinsulinemic-euglycemic clamp were performed to estimate glucose homeostasis in mice.The staining, including oil red O, hematoxylin & eosin, and BODIPY, and biochemical analysis for hepatic triglycerides were performed to assess hepatic lipids.Luciferase reporter assays, immunoprecipitation, immunoblots, quantitative real-time polymerase chain reaction, and immunohistochemistry staining were conducted to explore the underlying mechanism.Results: Here, we found that deficiency of PTP4A1 aggravated glucose homeostasis and hepatosteatosis in mice fed a high-fat (HF) diet.Increased lipid accumulation in hepatocytes of Ptp4a1 -/-mice reduced the level of glucose transporter 2 on the plasma membrane of hepatocytes leading to a diminution of glucose uptake.PTP4A1 prevented hepatosteatosis by activating the transcription factor cyclic adenosine monophosphate-responsive element-binding protein H (CREBH)/fibroblast growth factor 21 (FGF21) axis.Liver-specific PTP4A1 or systemic FGF21 overexpression in Ptp4a1 -/-mice fed an HF diet restored the disorder of hepatosteatosis and glucose homeostasis.Finally, liver-specific PTP4A1 expression ameliorated an HF diet-induced hepatosteatosis and hyperglycemia in wild-type mice.Conclusions: Hepatic PTP4A1 is critical for regulating hepatosteatosis and glucose homeostasis by activating the CREBH/FGF21 axis.Our current study provides a novel function of PTP4A1 in metabolic disorders; hence, modulating PTP4A1 may be a potential therapeutic strategy against hepatosteatosis-related diseases.
Retraction Note: Tumour-originated exosomal miR-155 triggers cancer-associated cachexia to promote tumour progression
Authors: Qi Wu, Si Sun, Zhiyu Li, Qian Yang, Bei Li, Shan Zhu, Lijun Wang, Juan Wu, Jingping Yuan, Changhua Yang, Juanjuan Li, Shengrong Sun
Journal: Molecular Cancer (2023)

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-018-0899-5.
Exploring neurotransmitters and their receptors for breast cancer prevention and treatment
Authors: Ruo Qi Li, Xiao Hong Zhao, Qin Zhu, Tao Liu, Hubert Hondermarck, Rick F. Thorne, Xu Dong Zhang, Jin Nan Gao
Journal: Theranostics (2023)

While psychological factors have long been linked to breast cancer pathogenesis and outcomes, accumulating evidence is revealing how the nervous system contributes to breast cancer development, progression, and treatment resistance.Central to the psychological-neurological nexus are interactions between neurotransmitters and their receptors expressed on breast cancer cells and other types of cells in the tumor microenvironment, which activate various intracellular signaling pathways.Importantly, the manipulation of these interactions is emerging as a potential avenue for breast cancer prevention and treatment.However, an important caveat is that the same neurotransmitter can exert multiple and sometimes opposing effects.In addition, certain neurotransmitters can be produced and secreted by non-neuronal cells including breast cancer cells that similarly activate intracellular signaling upon binding to their receptors.In this review we dissect the evidence for the emerging paradigm linking neurotransmitters and their receptors with breast cancer.Foremost, we explore the intricacies of such neurotransmitter-receptor interactions, including those that impinge on other cellular components of the tumor microenvironment, such as endothelial cells and immune cells.Moreover, we discuss findings where clinical agents used to treat neurological and/or psychological disorders have exhibited preventive/therapeutic effects against breast cancer in either associative or pre-clinical studies.Further, we elaborate on the current progress to identify druggable components of the psychological-neurological nexus that can be exploited for the prevention and treatment of breast cancer as well as other tumor types.We also provide our perspectives regarding future challenges in this field where multidisciplinary cooperation is a paramount requirement.
Single-cell spatial landscape of immunotherapy response reveals mechanisms of CXCL13 enhanced antitumor immunity
Authors: Mark Sorin, Elham Karimi, Morteza Rezanejad, Miranda W Yu, Lysanne Desharnais, Sheri A C McDowell, Samuel Doré, Azadeh Arabzadeh, Valerie Breton, Benoit Fiset, Yuhong Wei, Roni Rayes, Michele Orain, Francois Coulombe, Venkata S K Manem, Andreanne Gagne, Daniela F Quail, Philippe Joubert, Jonathan D Spicer, Logan A Walsh
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immunotherapy has revolutionized clinical outcomes for patients suffering from lung cancer, yet relatively few patients sustain long-term durable responses. Recent studies have demonstrated that the tumor immune microenvironment fosters tumorous heterogeneity and mediates both disease progression and response to immune checkpoint inhibitors (ICI). As such, there is an unmet need to elucidate the spatially defined single-cell landscape of the lung cancer microenvironment to understand the mechanisms of disease progression and identify biomarkers of response to ICI.Here, in this study, we applied imaging mass cytometry to characterize the tumor and immunological landscape of immunotherapy response in non-small cell lung cancer by describing activated cell states, cellular interactions and neighborhoods associated with improved efficacy. We functionally validated our findings using preclinical mouse models of cancer treated with anti-programmed cell death protein-1 (PD-1) immune checkpoint blockade.We resolved 114,524 single cells in 27 patients treated with ICI, enabling spatial resolution of immune lineages and activation states with distinct clinical outcomes. We demonstrated that CXCL13 expression is associated with ICI efficacy in patients, and that recombinant CXCL13 potentiates anti-PD-1 response in vivo in association with increased antigen experienced T cell subsets and reduced CCR2+ monocytes.Our results provide a high-resolution molecular resource and illustrate the importance of major immune lineages as well as their functional substates in understanding the role of the tumor immune microenvironment in response to ICIs.
<i>TIPE2</i>deletion improves the therapeutic potential of adoptively transferred NK cells
Authors: Jiacheng Bi, Chen Huang, Xiaomeng Jin, Chaoyue Zheng, Yingying Huang, Xiaohu Zheng, Zhigang Tian, Haoyu Sun
Journal: Journal for ImmunoTherapy of Cancer (2023)

To enhance the efficacy of adoptive NK cell therapy against solid tumors, NK cells must be modified to resist exhaustion in the tumor microenvironment (TME). However, the molecular checkpoint underlying NK cell exhaustion in the TME remains elusive. We analyzed the correlation between TIPE2 expression and NK cell functional exhaustion in the TME both in humans and mice by single-cell transcriptomic analysis and by using gene reporter mice. We investigated the effects of TIPE2 deletion on adoptively transferred NK cell therapy against cancers by using NK cells from NK-specific Tipe2-deficient mice or peripheral blood-derived or induced pluripotent stem cell (iPSC)-derived human NK cells with TIPE2 deletion by CRISPR/Cas9. We also investigated the potential synergy of double deletion of TIPE2 and another checkpoint molecule, CISH. By single-cell transcriptomic analysis and by using gene reporter mice, we found that TIPE2 expression correlated with NK cell exhaustion in the TME both in humans and mice and that the TIPE2 high NK cell subset correlated with poorer survival of tumor patients. TIPE2 deletion promoted the antitumor activity of adoptively transferred mouse NK cells and adoptively transferred human NK cells, either derived from peripheral blood or differentiated from iPSCs. TIPE2 deletion rendered NK cells with elevated capacities for tumor infiltration and effector functions. TIPE2 deletion also synergized with CISH deletion to further improve antitumor activity in vivo. This study highlighted TIPE2 targeting as a promising approach for enhancing adoptive NK cell therapy against solid tumors.
Decreasing the Effects of Aldosterone in Resistant Hypertension — A Success Story
Authors: Michel Azizi
Journal: New England Journal of Medicine (2023)

Despite the availability of several medications to treat hypertension, approximately 20% of patients with this condition have apparent resistant hypertension, which is defined as in-office systolic and diastolic blood pressure that is not decreased to less than 130/80 mmHg despite lifestyle measures and treatment with the maximum tolerated doses of three or more drugs, including a diuretic, a renin–angiotensin system blocker, and a calcium-channel blocker.1 Resistant hypertension is associated with an increased risk of premature cardiovascular events.1 The initial workup should rule out pseudo–resistant hypertension with the use of out-of-office blood-pressure measurements, nonadherence to antihypertensive medications, and secondary hypertension.1 Resistant . . .
Antiviral Agents against Omicron Subvariant BA.4.6 In Vitro
Authors: Jill Walker, Gretja Schnell, William Kerr
Journal: New England Journal of Medicine (2023)

Antiviral Agents against Omicron Subvariant BA.4.6 In VitroTo the Editor: Studies have shown that the neutralization activity of antibodies such as S309 (the precursor of sotrovimab) or sotrovimab, which bind outside the receptor-binding motif (RBM), depends on the expression level of the SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [ACE2]), whereas the activity of RBMtargeting monoclonal antibodies is not considerably affected by ACE2 receptor expression. 1,2hree recent letters in the Journal from a group at the University of Tokyo (Aug. 4 and Dec. 1, 2022, and Jan. 5, 2023, issues) 3-5 reported substantial loss of in vitro neutralization activity with S309 against recent B.1.1.529(omicron) variants.This group cites the use of VeroE6 cells overexpressing nonphysiologic levels of both the ACE2 receptor and TMPRSS2 protease as target cells for neutralization assays.The lack of activity with S309 reflects the use of assay conditions that are known to substantially underestimate S309 or sotrovimab neutralization and thus do not represent the actual activity of the molecule against a particular SARS-CoV-2 viral variant.Table 1 contrasts the 50% focus reduction neutralization test (FRNT 50 ) or half maximal effective concentration (EC 50 ) and factor-change data from the University of Tokyo group with data from other sources that used an appropriate cell type for sotrovimab or S309.